Intracutaneous microneedle array apparatus

ABSTRACT

A first embodiment microneedle array is constructed of silicon and silicon dioxide compounds using MEMS technology and standard microfabrication techniques to create hollow cylindrical individual microneedles. The resulting array of microneedles can penetrate with a small pressure through the stratum corneum of skin to either deliver drugs or to facilitate interstitial fluid sampling through the hollow microneedles into the epidermis. The delivery of drugs and sampling of fluids can be performed by way of passive diffusion (time release), instantaneous injection, or iontophoresis. In a second embodiment, an array of hollow (or solid) microneedles is constructed of plastic or some other type of molded or cast material. An electric field may be used to increase transdermal flow rate, and the microneedles can be effectively combined with the application of an electric field between an anode and cathode attached to the skin which causes a low-level electric current. As a drug delivery system, the microneedle array includes electrodes that apply an electric potential to the skin between the electrode locations. One of the electrode assemblies is filled with an ionized drug, and the charged drug molecules move into the body due to the applied electric potential. As a body-fluid sampling system, the microneedle array also includes electrodes to assist in moving fluid from the body into a receiving chamber, and which further includes a bioelectrochemical sensor to measure the concentration of a particular substance.

TECHNICAL FIELD

The present invention relates generally to medical devices and isparticularly directed to a fluid dispensing device and a fluid samplingdevice of the type which penetrates the stratum corneum and epidermis,but not into the dermis of skin. The invention is specifically disclosedas an array of microneedles which painlessly and with minimal trauma tothe skin enable fluid transfer either into a body as a dispensingdevice, or from the body to sample body fluid.

BACKGROUND OF THE INVENTION

Topical delivery of drugs is a very useful method for achieving systemicor localized pharmacological effects. The main challenge intranscutaneous drug delivery is providing sufficient drug penetrationacross the skin. The skin consists of multiple layers starting with astratum corneum layer about (for humans) twenty (20) microns inthickness (comprising dead cells), a viable epidermal tissue layer aboutseventy (70) microns in thickness, and a dermal tissue layer about two(2) mm in thickness.

The thin layer of stratum corneum represents a major barrier forchemical penetration through skin. The stratum corneum is responsiblefor 50% to 90% of the skin barrier property, depending upon the drugmaterial's water solubility and molecular weight. The epidermiscomprises living tissue with a high concentration of water. This layerpresents a lesser barrier for drug penetration. The dermis contains arich capillary network close to the dermal/epidermal junction, and oncea drug reaches the dermal depth it diffuses rapidly to deep tissuelayers (such as hair follicles, muscles, and internal organs), orsystemically via blood circulation.

Current topical drug delivery methods are based upon the use ofpenetration enhancing methods, which often cause skin irritation, andthe use of occlusive patches that hydrate the stratum corneum to reduceits barrier properties. Only small fractions of topically applied drugpenetrates through skin, with very poor efficiency.

Convention methods of biological fluid sampling and non-oral drugdelivery are normally invasive. That is, the skin is lanced in order toextract blood and measure various components when performing fluidsampling, or a drug delivery procedure is normally performed byinjection, which causes pain and requires special medical training. Analternative to drug delivery by injection has been proposed by Henry,McAllister, Allen, and Prausnitz, of Georgia Institute of Technology (ina paper titled “Micromachined Needles for the Transdermal Delivery ofDrugs), in which an array of solid microneedles is used to penetratethrough the stratum corneum and into the viable epidermal layer, but notto the dermal layer. In this Georgia Tech design, however, the fluid isprone to leakage around the array of microneedles, since the fluid is onthe exterior surface of the structure holding the microneedles.

Another alternative to drug delivery by injection is disclosed in U.S.Pat. No. 3,964,482 (by Gerstel), in which an array of either solid orhollow microneedles is used to penetrate through the stratum corneum,into the epidermal layer, but not to the dermal layer. Fluid is to bedispensed either through hollow microneedles, through permeable solidprojections, or around non-permeable solid projections that aresurrounded by a permeable material or an aperture. A membrane materialis used to control the rate of drug release, and the drug transfermechanism is absorption. The microneedle size is disclosed as having adiameter of 15 gauge through 40 gauge (using standard medical gaugeneedle dimensions), and a length in the range of 5-100 microns. Thepermeable material may be filled with a liquid, hydrogel, sol, gel, ofthe like for transporting a drug through the projections and through thestratum corneum.

Another structure is disclosed in WO 98/00193 (by Altea Technologies,Inc.) in the form of a drug delivery system, or analyte monitoringsystem, that uses pyramidal-shaped projections that have channels alongtheir outer surfaces. These projections have a length in the range of30-50 microns, and provide a trans-dermal or trans-mucous deliverysystem, which can be enhanced with ultrasound.

Another structure, disclosed in WO 97/48440, WO 97/48441, and WO97/48442 (by ALZA Corp.) is in the form of a device for enhancingtransdermal agent delivery or sampling. It employs a plurality of solidmetallic microblades and anchor elements, etched from a metal sheet,with a length of 25-400 mm. WO 96/37256 (by Silicon Microdevices, Inc.)disclosed another silicon microblade structure with blade lengths of10-20 mm. For enhancing transdermal delivery.

Most of the other conventional drug delivery systems involve an invasiveneedle or plurality of needles. An example of this is U.S. Pat. No.5,848,991 (by Gross) which uses a hollow needle to penetrate through theepidermis and into the dermis of the subject's skin when the housingcontaining an expansible/contractible chamber holding a reservoir offluidic drug is attached to the skin. Another example of this is U.S.Pat. No. 5,250,023 (by Lee) which administers fluidic drugs using aplurality of solid needles that penetrate into the dermis. The Lee drugdelivery system ionizes the drug to help transfer the drug into the skinby an electric charge. The needles are disclosed as being within therange of 200 microns through 2,000 microns.

Another example of a needle that penetrates into the dermis is providedin U.S. Pat. No. 5,591,139, WO 99/00155, and U.S. Pat. No. 5,855,801 (byLin) in which the needle is processed using integrated circuitfabrication techniques. The needles are disclosed as having a length inthe range of 1,000 microns through 6,000 microns.

The use of microneedles has great advantages in that intracutaneous drugdelivery can be accomplished without pain and without bleeding. As usedherein, the term “microneedles” refers to a plurality of elongatedstructures that are sufficiently long to penetrate through the stratumcorneum skin layer and into the epidermal layer, yet are alsosufficiently short to not penetrate to the dermal layer. Of course, ifthe dead cells have been completely or mostly removed from a portion ofskin, then a very minute length of microneedle could be used to reachthe viable epidermal tissue.

Since microneedle technology shows much promise for drug delivery, itwould be a further advantage if a microneedle apparatus could beprovided to sample fluids within skin tissue. Furthermore, it would be afurther advantage to provide a microneedle array in which the individualmicroneedles were of a hollow structure so as to allow fluids to passfrom an internal chamber through the hollow microneedles and into theskin, and were of sufficient length to ensure that they will reach intothe epidermis, entirely through the stratum corneum.

SUMMARY OF THE INVENTION

Accordingly, it is a primary advantage of the present invention toprovide a microneedle array in the form of a patch which can performintracutaneous drug delivery. It is another advantage of the presentinvention to provide a microneedle array in the form of a patch that canperform interstitial body-fluid testing and/or sampling. It is a furtheradvantage of the present invention to provide a microneedle array aspart of a closed-loop system to control drug delivery, based on feedbackinformation that analyzes body fluids, which can achieve real timecontinuous dosing and monitoring of body activity. It is yet anotheradvantage of the present invention to provide aniontophoretically/microneedle-enhanced transdermal drug delivery systemin order to achieve high-rate drug delivery and to achieve sampling ofbody fluids. It is a yet further advantage of the present invention toprovide a method for manufacturing an array of microneedles usingmicrofabrication techniques, including standard semiconductorfabrication techniques. It is still another advantage of the presentinvention to provide a method of manufacturing an array of microneedlescomprising a plastic material by a “self-molding” method, a micromoldingmethod, a microembossing method, or a microinjection method.

Additional advantages and other novel features of the invention will beset forth in part in the description that follows and in part willbecome apparent to those skilled in the art upon examination of thefollowing or may be learned with the practice of the invention.

To achieve the foregoing and other advantages, and in accordance withone aspect of the present invention, a first embodiment of an improvedmicroneedle array is constructed of silicon and silicon dioxidecompounds using MEMS (i.e., Micro-Electro-Mechanical-Systems) technologyand standard microfabrication techniques. The microneedle array may befabricated from a silicon die which can be etched in a microfabricationprocess to create hollow cylindrical individual microneedles. Theresulting array of microneedles can penetrate with a small pressurethrough the stratum corneum of skin (including skin of animals,reptiles, or other creatures-typically skin of a living organism) toeither deliver drugs or to facilitate interstitial fluid samplingthrough the hollow microneedles. The drug reservoir, and/or the chemicalanalysis components for sampling body fluid, may be fabricated insidethe silicon die, or an additional thick film layer can be bonded orotherwise attached over the silicon substrate to create the reservoir.The delivery of drugs and sampling of fluids can be performed by way ofpassive diffusion (e.g., time release), instantaneous injection, oriontophoresis. A complete closed-loop system can be manufacturedincluding active elements, such as micro-machined pumps, heaters, andmixers, as well as passive elements such as sensors. A “smart patch” canthereby be fabricated that samples body fluids, performs chemistry todecide on the appropriate drug dosage, and then administers thecorresponding amount of drug. Such a system can be made disposable,including one with an on-board power supply.

In a second embodiment, an array of hollow (or solid) microneedles canbe constructed of plastic or some other type of molded or cast material.When using plastic, a micro-machining technique is used to fabricate themolds for a plastic microforming process. The molds are detachable andcan be re-used. Since this procedure requires only a one-time investmentin the mold micro-machining, the resulting plastic microstructure shouldbe much less expensive than the use of microfabrication techniques toconstruct microneedle arrays, as well as being able to manufactureplastic microneedle arrays much more quickly. It will be understood thatsuch hollow microneedles may also be referred to herein as “hollowelements,” or “hollow projections,” including in the claims. It willalso be understood that such solid microneedles may also be referred toherein as “solid elements,” or “solid projections” (or merely“projections”), including in the claims.

Molds used in the second embodiment of the present invention can containa micropillar array and microhole array (or both), which are fabricatedby micro-machining methods. Such micro-machining methods may includemicro electrode-discharge machining to make the molds from a variety ofmetals, including stainless steel, aluminum, copper, iron, tungsten, andtheir alloys. The molds alternatively can be fabricated bymicrofabrication techniques, including deep reactive etching to makesilicon, silicon dioxide, and silicon carbide molds. Also, LIGA or deepUV processes can be used to make molds and/or electroplated metal molds.

The manufacturing procedures for creating plastic (or other moldablematerial) arrays of microneedles include: “self-molding,” micromolding,microembossing, and microinjection techniques. In the “self-molding”method, a plastic film (such as a polymer) is placed on a micropillararray, the plastic is then heated, and plastic deformation due togravitational force causes the plastic film to deform and create themicroneedle structure. Using this procedure, only a single mold-half isrequired. When using the micromolding technique, a similar micropillararray is used along with a second mold-half, which is then closed overthe plastic film to form the microneedle structure. The micro-embossingmethod uses a single mold-half that contains an array of micropillarsand conical cut-outs (microholes) which is pressed against a flatsurface (which essentially acts as the second mold-half) upon which theplastic film is initially placed. In the microinjection method, a meltedplastic substance is injected between two micromachined molds thatcontain microhole and micropillar arrays.

Of course, instead of molding a plastic material, the microneedle arraysof the present invention could also be constructed of a metallicmaterial by a die casting method using some of the same structures asare used in the molding techniques discussed above. Since metal issomewhat more expensive and more difficult to work with, it is probablynot the preferred material except for some very stringent requirementsinvolving unusual chemicals or unusual application or placementcircumstances. The use of chemical enhancers, ultrasound, or electricfields may also be used to increase transdermal flow rate when used withthe microneedle arrays of the present invention.

In the dispensing of a liquid drug, the present invention can beeffectively combined with the application of an electric field betweenan anode and cathode attached to the skin which causes a low-levelelectric current. The present invention combines the microneedle arraywith iontophoresis enhancement, which provides the necessary means formolecules to travel through the thicker dermis into or from the body,thereby increasing the permeability of both the stratum corneum anddeeper layers of skin. While the transport improvement through thestratum corneum is mostly due to microneedle piercing, iontophoresisprovides higher transport rates in epidermis and dermis.

The present invention can thereby be used with medical devices todispense drugs by iontophoretic/microneedle enhancement, to sample bodyfluids (while providing an iontophoretically/microneedle-enhancedbody-fluid sensor), and a drug delivery system with fluid samplingfeedback using a combination of the other two devices. For example, thebody-fluid sensor can be used for a continuous noninvasive measurementof blood glucose level by extracting glucose through the skin by reverseiontophoresis, and measuring its concentration using abioelectrochemical sensor. The drug delivery portion of this inventionuses the microneedle array to provide electrodes that apply an electricpotential between the electrodes. One of the electrodes is also filledwith an ionized drug, and the charged drug molecules move into the bodydue to the applied electric potential.

Still other advantages of the present invention will become apparent tothose skilled in this art from the following description and drawingswherein there is described and shown a preferred embodiment of thisinvention in one of the best modes contemplated for carrying out theinvention. As will be realized, the invention is capable of otherdifferent embodiments, and its several details are capable ofmodification in various, obvious aspects all without departing from theinvention. Accordingly, the drawings and descriptions will be regardedas illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings incorporated in and forming a part of thespecification illustrate several aspects of the present invention, andtogether with the description and claims serve to explain the principlesof the invention. In the drawings:

FIG. 1 is an elevational view in partial cross-section of a bottom moldprovided at the initial step of a “self-molding” method of manufacturingan array of plastic microneedles, as constructed according to theprinciples of the present invention.

FIG. 2 is an elevational view in partial cross-section of the mold ofFIG. 1 in a second step of the self-molding procedure.

FIG. 3 is an elevational view in partial cross-section of the mold ofFIG. 1 in a third step of the self-molding procedure.

FIG. 4 is an elevational view in partial cross-section of the mold ofFIG. 1 in a fourth step of the self-molding procedure.

FIG. 5 is an elevational view in partial cross-section of the mold ofFIG. 1 in a fifth step of the self-molding procedure.

FIG. 6 is an elevational view in cross-section of an array of hollowmicroneedles constructed according to the self-molding proceduredepicted in FIGS. 1-5.

FIG. 7 is a cross-sectional view of a top mold-half used in amicromolding procedure, according to the principles of the presentinvention.

FIG. 8 is an elevational view of the bottom half of the mold that matesto the top mold-half of FIG. 7, and which is used to form plasticmicroneedles according to the micromolding procedure.

FIG. 9 is an elevational view in partial cross-section of one of themethod steps in the micromolding procedure using the mold halves ofFIGS. 7 and 8.

FIG. 10 is an elevational view in partial cross-section of the mold ofFIG. 9 depicting the next step in the micromolding procedure.

FIG. 11 is a cross-sectional view of an array of plastic microneedlesconstructed according to the micromolding procedure depicted in FIGS.7-10.

FIG. 12 is an elevational view in partial cross-section of a topmold-half and a bottom planar surface used in creating an array ofmolded, plastic microneedles by a microembossing procedure, asconstructed according to the principles of the present invention.

FIG. 13 is an elevational view in partial cross-section of the mold ofFIG. 12 in a subsequent process step of the microembossing method.

FIG. 14 is an elevational view in partial cross-section of the mold ifFIG. 12 showing a later step in the microembossing procedure.

FIG. 15 is a cross-sectional view of a microneedle array of hollowmicroneedles constructed by the mold of FIGS. 12-14.

FIG. 15A is a cross-sectional view of an array of microneedles which arenot hollow, and are constructed according to the mold of FIGS. 12-14without the micropillars.

FIG. 16 is an elevational view in partial cross-section of a two-piecemold used in a microinjection method of manufacturing plasticmicroneedles, as constructed according to the principles of the presentinvention.

FIG. 17 is a cross-sectional view of a microneedle array of hollowmicroneedles constructed by the mold of FIG. 16.

FIG. 18 is a cross-sectional view of the initial semiconductor waferthat will be formed into an array of microneedles by a microfabricationprocedure, according to the principles of the present invention.

FIG. 19 is a cross-sectional view of the semiconductor wafer of FIG. 18after a hole pattern has been established, and after a silicon nitridelayer has been deposited.

FIG. 20 is a cross-sectional view of the wafer of FIG. 18 after aphotoresist mask operation, a deep reactive ion etch operation, and anoxidize operation have been performed.

FIG. 21 is a cross-sectional view of the wafer of FIG. 20 after thesilicon nitride has been removed, and after a deep reactive ion etch hascreated through holes, thereby resulting in a hollow microneedle.

FIG. 22 is a perspective view of a microneedle array on a semiconductorsubstrate, including a magnified view of individual cylindricalmicroneedles.

FIG. 23 is a cross-sectional view of an iontophoretically enhancedbody-fluid sensor, based upon a hollow microneedle array, as constructedaccording to the principles of the present invention.

FIG. 24 is a cross-sectional view of an iontophoretically enhancedbody-fluid sensor, based upon a solid microneedle array, as constructedaccording to the principles of the present invention.

FIG. 25 is a cross-sectional view of an electrode, based upon a hollowmicroneedle array, as constructed according to the principles of thepresent invention.

FIG. 26 is a cross-sectional view of an electrode, based upon a solidmicroneedle array, as constructed according to the principles of thepresent invention.

FIG. 27 is a perspective view of a sensing system attached to a humanhand and forearm, which includes an iontophoretically enhancedbody-fluid sensor as per FIG. 23 and an electrode as per FIG. 25.

FIG. 28 is a cross-sectional view of an iontophoretically enhanced drugdelivery system, based upon a hollow microneedle array, as constructedaccording to the principles of the present invention.

FIG. 29 is a cross-sectional view of an iontophoretically enhanced drugdelivery system, based upon a solid microneedle array, as constructedaccording to the principles of the present invention.

FIG. 30 is a perspective view of a closed-loop drug-delivery system, asviewed from the side of a patch that makes contact with the skin, asconstructed according to the principles of the present invention.

FIG. 31 is a perspective view of the closed-loop drug-delivery system ofFIG. 30, as seen from the opposite side of the patch.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Reference will now be made in detail to the present preferred embodimentof the invention, an example of which is illustrated in the accompanyingdrawings, wherein like numerals indicate the same elements throughoutthe views.

Referring now to the drawings, FIG. 1 shows a mold generally designatedby the reference numeral 10 that comprises a plurality of micropillars,including micropillars 12 and 14, that are mounted to a base 16 having aplanar upper surface 18. Micropillar 12 preferably is cylindrical inshape, and has an outer diameter a, designated “D1,” whereas micropillar14 (which also preferably is cylindrical in shape) has a diameterdesignated “D2.” The centerlines of micropillars 12 and 14 are separatedby a distance “D3,” and the vertical height of micropillars 12 and 14 isdesignated by the letter “L1.”

In a preferred configuration, the diameters D1 and D2 are in the rangeof 1-49 microns, more preferably about ten (10) microns (i.e., 10microns=10 micrometers), the height L1 in the range of 50-200 microns,whereas the separation distance D3 is in the range of 50-1000 microns,more preferably from 50-200 microns.

Microelectrode-discharge machining can be used to fabricate the mold 10from metals, such as stainless steel, aluminum, copper, iron, tungsten,or other metal alloys. Mold 10 could also be fabricated from silicon orsilicon carbide using integrated circuit processing, orphotolithographic processing.

FIG. 2 depicts the mold 10 and a thin layer of plastic, such as apolymer film, designated by the reference numeral 20, which is placed onthe micropillars 12 and 14, thereby making contact at the referencenumerals 22 and 24, respectively. Once the polymer film is placed on themicropillars, the polymer is heated to just above the meltingtemperature of the plastic material. Micropillars 12 and 14 are alsoheated to a certain extent, but are held just below the meltingtemperature of the plastic material. This establishes a temperaturegradient within the plastic film, after which the plastic film issubjected to natural gravitational forces, or placed in a centrifuge.Furthermore, an air-pressure gradient also can be established across thedeforming plastic film, by applying pressure from above, or by applyinga vacuum from below the film level. The overall effect on the plasticfilm is that it will undergo a “self-molding” operation, by way of thegravitational force or centrifugal force, and the air-pressure gradientcan be used to accelerate the self-molding process.

FIG. 3 depicts the mold 10 at a further step in the processing of theplastic film, showing the result of the temperature gradient. Thisresult is that the areas contacting the micropillars (at the referencenumerals 22 and 24) will have a smaller deformation as compared to theremaining portions of the plastic film 20 that are between the pillars12 and 14. Therefore, the portions 30, 32, and 34 of the plasticmaterial will undergo greater deformation, as viewed on FIG. 3.

FIG. 4 depicts the mold 10 at yet a later step in the self-moldingprocess, showing the initial stage in which the mold (includingmicropillars 12 and 14) is heated above the melting temperature of theplastic material 20. During this latter stage of the self-moldingprocess, the plastic material will continue to melt and to be removedfrom the tops of the pillars 12 and 14. As viewed in FIG. 4, theremaining portions not in contact with micropillars 12 and 14 willcontinue to deform downward (as viewed on FIG. 4) at the referencenumerals 30, 32, and 34.

FIG. 5 depicts the mold 10 at the final stage of self-molding, whichillustrates the fact that the plastic material has completely melteddown and away from the tops 22 and 24 of the micropillars 12 and 14. Atthis point the mold and the plastic material are both cooled down,thereby forming the final shape that will become the microneedles. Thisfinal shape includes an outer wall 40 and 42 for the microneedle beingformed by micropillar 12, and an outer wall at 44 and 46 for themicroneedle being formed at the micropillar 14.

FIG. 6 illustrates the cross-sectional shape of the microneedle array,generally designated by the reference numeral 60, after it has beendetached from the mold 10. The left hand microneedle 62 has a relativelysharp upper edge, which appears as points 50 and 52. Its outer wall isillustrated at 40 and 42, which are sloped with respect to the vertical,as designated by the angles “A1” and “A2.” The right-hand sidemicroneedle 64 exhibits a similar sharp top edge, as indicated by thepoints 54 and 56, and also exhibits a sloped outer wall at 44 and 46.The angle of this outer wall is indicated at the angles “A3” and “A4.”The preferred value of angles A1-A4 is in the range of zero (0) toforty-five (45) degrees.

The inner diameter of the left-hand microneedle 62 is indicated by thedistance “D1,” and the inner diameter of the right-hand microneedle 64is indicated by the distance “D2.” These distances D1 and D2 aresubstantially the same distance as the diameter of micropillars 12 and14, as indicated in FIG. 1. Furthermore, the distance D3 between thecenterlines of the microneedles on FIG. 6 is essentially the same as thedistance D3 between the micropillars on FIG. 1. The length “L2” of themicroneedles on FIG. 6 is somewhat less than the length L1 on FIG. 1,although this length L2 could theoretically be a maximum distance of L1.

It will be understood that the plastic material (also referred to hereinas the “polymer film”) may consist of any type of permanently deformablematerial that is capable of undergoing a gradual deformation as itsmelting point is reached or slightly exceeded. This “plastic material”could even be some type of metallic substance in a situation where themetallic material would deform at a low enough temperature so as to notharm the mold itself. The preferred material is a polyamide such asnylon, although many other types of polymer material certainly could beused to advantage. Other potential materials include: polyesters, vinyl,polysterene, polycarbonate, and acrylonitrilebutadisterene (ABS). Ofcourse, one important criterion is that the material which makes up themicroneedles does not chemically react with skin, or with the fluidicsubstance that is being transported through the hollow interiors of themicroneedle array.

FIG. 7 depicts a top mold-half, generally designated by the referencenumeral 110, of a second embodiment of the present invention in whichthe manufacturing method for creating an array of hollow microneedles isperformed by a micromolding procedure. The top mold-half 110 includestwo “microholes” that have sloped side walls, designated by thereference numerals 112 and 114 for the left-hand microhole 113, and bythe reference numerals 116 and 118 for the right-hand microhole 117. Themicroholes 113 and 117 have a vertical (in FIG. 7) dimension referred toherein as a distance “L11”. Microholes 113 and 117 correspond to a pairof micropillars 122 and 124 that are part of a bottom mold-half,generally designated by the reference number 120, and illustrated inFIG. 8.

Referring back to FIG. 7, the sloped side walls of the microhole 113 aredepicted by the angles “A11” and “A12,” with respect to the vertical.The side walls of microhole 117 are also sloped with respect to thevertical, as illustrated by the angles “A13” and “A14” on FIG. 7. Sincemicrohole 113 preferably is in a conical overall shape, the angle A11will be equal to the angle A12; similarly for microhole 117, the angleA13 will be equal to the angle A14. It is preferred that all microholesin the top mold-half 110 exhibit the same angle with respect to thevertical, which means that angles A11 and A13 are also equal to oneanother. A preferred value for angles A11-A14 is in the range of zero(0) through forty-five (45) degrees. The larger the angle from thevertical, the greater the trauma to the skin tissue when a microneedleis pressed against the skin. On FIG. 7, the illustrated angle A11 isapproximately twelve (12) degrees.

Referring now to FIG. 8, the bottom mold-half 120 includes a base 126having a substantially planar top surface 128, upon which the twomicropillars 122 and 124 are mounted. These micropillars are preferablycylindrical in shape, and have a diameter of D11 and D12, respectively.The distance between the centerlines of these micropillars is designatedas D13. Diameters D11 and D12 preferably are in the range 1-49 microns,more preferably about 10 microns. The distance “D13” represents theseparation distance between the center lines of micropillars 122 and124, which preferably is in the range 50-1000 microns, more preferablyabout 200 microns.

The two mold-halves 110 and 120 can be fabricated from metals usingmicroelectrode-discharge machining techniques. Alternatively, the moldscould be fabricated from silicon or silicon carbide using integratedcircuit processing or lithographic processing.

On FIG. 8, a thin plastic film, generally designated by the referencenumeral 130, is placed on top of the micropillars and heated above theglass transition temperature of the plastic material while the plasticmaterial 130 rests upon the tops of the pillars at 132 and 134, therebycausing the plastic material to become sufficient pliable or “soft” forpurposes of permanently deforming the material's shape. Preferably, thetemperature of the plastic material will not be raised above its meltingtemperature, although it would not inhibit the method of the presentinvention for the plastic material to become molten just before the nextstep of the procedure. In FIG. 9, the top mold-half 110 is presseddownward and begins to deform the plastic film 130. While a portion ofthe plastic material 130 temporarily resides above the micropillars at132 and 134, a larger amount of the plastic material is pressed downwarddirectly by the mold top-half 110 at 140, 142, and 144. As can be seenin FIG. 9, the two mold halves 110 and 120 are aligned so that themicroholes 113 and 117 correspond axially to the micropillars 122 and124, respectively. The two mold halves now begin to operate as a singlemold assembly, generally designated by the reference numeral 100.

In FIG. 10, the two mold halves 110 and 120 have completely closed,thereby squeezing all of the plastic material 130 away from the tops ofthe micropillars 122 and 124. At this point, the plastic microneedlesare formed, and the mold and the plastic material are both cooled down.

The wall 112 and 114 of the first microhole 113 causes a side outer wallto be formed out of the plastic material at 150 and 152. Thecorresponding inner wall of the microneedle 182 is depicted at 160 and162, which is caused by the shape of the micropillar 122. Since theouter wall is sloped, it will converge with the inner wall 160 and 162,near the top points at 170 and 172. A similar outer wall 154 and 156 isformed by the inner wall 116 and 118 of microhole 117. The inner wall ofthe microneedle 184 is depicted at 164 and 166, and these inner andouter walls converge near points 174 and 176.

FIG. 11 illustrates the microneedle array, generally designated by thereference numeral 180, after the mold is removed from the plasticmaterial 130. A lower relatively planar base remains, as illustrated at140, 142, and 144. On FIG. 11, two different microneedles are formed at182 and 184. The angles formed by the walls are as follows: angle All bywalls 150 and 160, angle A12 by walls 162 and 152, angle A13 by walls154 and 164, and angle A14 by walls 166 and 156. The points at the topif the microneedles (designated at 170, 172, 174, and 176) are fairlysharp, and this sharpness can be adjusted by the shape of the mold withrespect to the microholes and micropillar orientations.

The inner diameter of microneedle 182 is designated by the distance D11,and the inner diameter of the microneedle 184 is designated by thedistance D12. The distance between the centerlines of these microneedlesis designated as D13. These distances correspond to those illustrated onFIG. 8.

It is preferred that all of the angles A11-A14 are equal to one another,and that the angles fall within the range of zero (0) to forty-five (45)degrees. The preferred angle really depends upon the strength of thematerial being used to construct the microneedles, in which a greaterangle (e.g., angle A11) provides greater strength. However, this angularincrease also causes greater trauma to the skin.

Microneedle array 180 also includes a relatively flat base structure, asindicated at the reference numerals 140, 142, and 144. This basestructure has a vertical thickness as designated by the dimension L15(see FIG. 11). The microneedle height is designated by the dimension L12on FIG. 11. The height must be sufficient to penetrate the skin throughthe stratum corneum and into the epidermis, and a preferred dimensionfor height L12 is in the range of 50-200 microns (although, certainlymicroneedles shorter than 50 microns in length could be constructed inthis manner—for use with skin cosmetics, for example). The thickness L15can be of any size, however, the important criterion is that it be thickenough to be mechanically sound so as to retain the microneedlestructure as it is used to penetrate the skin.

Referring now to FIG. 12, a top mold-half 210 is combined with a planarbottom mold-half 240 to create an entire mold, generally designated bythe reference numeral 200. The top mold-half 210 contains an array ofmicroholes with micropillars at the center of each of the microholes.For example, a microhole 213, having its conical wall at 212 and 214, ispreferably concentric with a micropillar 222, and a microhole 217,having its conical wall at 216 and 218, is preferably concentric with amicropillar 224.

The fabrication method used in conjunction with the mold 200 is referredto herein as “microembossing” for the reason that the bottom mold-half240 is simply a flat or planar surface. This greatly simplifies theconstruction of this particular mold. A thin plastic film at 230 isplaced upon the top surface 242 of this bottom mold-half 240. In thelater steps, it will be seen that the plastic material 230 is heatedwhile the top mold-half 210 is pressed down against the bottom mold-half240.

Microhole 213 and micropillar 222 have an angular relationship asillustrated by the angles “A21” and “A22.” A similar angularrelationship exists for microhole 217 and micropillar 224, asillustrated by the angles “A23” and “A24.” These angles A21-A24 willpreferably be in the range of zero (0) to forty-five (45) degrees fromthe vertical. As noted hereinabove, the greater the angle, the greaterthe transport rate, however, also the greater trauma to the skin tissuewhen used.

Micropillar 222 preferably has a cylindrical shape with an outerdiameter designated at “D21,” and micropillar 224 similarly has apreferred cylindrical shape having a diameter “D22.” Diameters D21 andD22 preferably are in the range 1-49 microns, more preferably about 10microns. The distance “D23” represents the separation distance betweenthe center lines of micropillars 222 and 224, which preferably is in therange 50-1000 microns, more preferably about 200 microns.

The length of the micropillars from the bottom surface 228 of the topmold-half 210 to the closed end of the microholes at 215 and 225,respectively, is designated as the length “L21.” The micropillars 222and 224 are somewhat longer than this length L21, since they are to mateagainst the upper surface 242 of the bottom mold-half 240, and thereforeare longer by a distance designated as “L25.” In this manner, themicroneedles will be hollow throughout their entire length. The combinedlength of dimensions L21 and L25 preferably will be approximately 150microns.

The molds 210 and 240 will preferably be made from a metal, in whichmicroelectrode-discharge machining can be used to fabricate suchmetallic molds. Alternatively, the molds could be fabricated fromsilicon or silicon carbide, for example, using integrated circuitprocessing or lithographic processing.

Referring now to FIG. 13, after the plastic material is heated above itsglass transition temperature, thereby causing the plastic material tobecome sufficient pliable or “soft” for purposes of permanentlydeforming the material's shape. Preferably, the temperature of theplastic material will not be raised above its melting temperature,although it would not inhibit the method of the present invention forthe plastic material to become molten just before the top mold 210begins to be pressed down against the plastic material 230. This topmold movement begins to deform that plastic material 230 such that itbegins to fill the microholes, as illustrated at 232 and 234 (formicrohole 213) and at 236 and 238 (for microhole 217).

In FIG. 14, the top mold-half 210 has now been completely closed againstthe bottom planar mold-half 240, and the plastic material 230 has nowcompletely filled the microholes, as illustrated at 232, 234, 236, and238. The shape of the plastic material now has a conical outer wall at250 and 252, and a corresponding cylindrical inner wall at 260 and 262,for the left-hand microneedle 282 on FIG. 14. Correspondingly for theright-hand microneedle 284, the plastic material shape has an outerconical wall at 254 and 256, as well as a cylindrical inner wall at 264and 266. The conical outer walls and the cylindrical inner wallsconverge at the top points 270 and 272, and 274 and 276. The bottomsurface 228 of the top mold-half 210 causes a base to be formed in theplastic material 230 at the locations indicated by the referencenumerals 244, 246, and 248. Once this shape has been formed, the moldand the plastic material are cooled down, and then the molds areseparated so that the plastic microneedle array is detached to form theshape as illustrated in FIG. 15.

In FIG. 15, a microneedle array 280 has been formed out of the plasticmaterial 230, which as viewed on FIG. 15 depicts two microneedles 282and 284. The left-hand microneedle 282 comprises an outer conical wallas viewed at 250 and 252, and a hollow interior cylindrical wall at 260and 262. These walls converge at the top points (as viewed on thisFigure) at 270 and 272, and the convergence angle is given as “A21” and“A22.” The right-hand microneedle 284 comprises an outer conical wall254 and 256 and a hollow interior cylindrical wall 262 and 264. Thesewalls converge at the top points (on this Figure) at 274 and 276, andthe convergence angle is given as “A23” and “A24.” Angles A21-A24 arepreferably in the range of zero (0) to forty-five (45) degrees.

Microneedle array 280 also includes a relatively flat base structure, asindicated at the reference numerals 244, 246, and 248. This basestructure has a vertical thickness as designated by the dimension L25.The microneedle height is designated by the dimension L22. The heightmust be sufficient to penetrate the skin through the stratum corneum andinto the epidermis, and has a preferred dimension in the range of 50-200microns (although, as noted above, much shorter microneedles could beconstructed in this manner). The thickness L25 can be of any size,however, the important criterion is that it be thick enough to bemechanically sound so as to retain the microneedle structure as it isused to penetrate the skin.

The inside diameter of the hollow microneedles is illustrated as D21 andD22, which correspond to the diameters of a cylindrical hollow opening.The distance D23 represents the separation distance between thecenterlines of the two microneedles 282 and 284, in this array 280.

FIG. 15A represents an alternative embodiment in which a microneedlearray 290 comprises “solid” microneedles 292 and 294, rather than hollowmicroneedles as seen at 282 and 284 on FIG. 15. These solid microneedles292 and 294 are formed by a similar mold as viewed on FIG. 12, but withthe micropillars 222 and 224 removed from this mold, and a change inshape of the microholes 213 and 217. This simple change allows the solidmicroneedles to be formed within conical microholes (not shown on FIG.12), and produces a pointed conical shape, as exhibited by the outerconical wall 250 and 252 for microneedle 292, with a top pointed surfaceat 296. Similarly, the microneedle 294 has a conical outer wall 254 and256, with a similar top pointed surface at 298. The other dimensions andfeatures of the solid microneedle array 290 can be exactly the same asthose features of the hollow microneedle array 280 of FIG. 15, or thedimensions may be different since this is for a different application.

The holes 251, 253, 255, can be fabricated during the microstamping ormicrembossing procedure via inclusion of appropriate micropillarslocated adjacent to the microholes 213 and 217 in FIG. 12.

Referring to FIG. 16, a mold 300 consists of two mold-halves 310 and340. These mold-halves 310 and 340 are virtually identical in shape, andprobably in size, as compared to the mold-halves 210 and 240 of the mold200 on FIG. 12. The main difference in FIG. 16 is that these mold-halvesare to be used in a microinjection procedure in which molten plasticmaterial is injected from the side at 330 into the opening between themold-halves formed by the bottom surface 328 of the top mold-half 310and the top surface 342 of the bottom mold-half 340.

The mold structure 300 is preferably made of a metallic material by amicromachining process, although it could be made of a semiconductormaterial such as silicon or silicon carbide, if desired. On FIG. 16, theplastic material 330 is being filled from the left-hand side in thisview, and has already filled a first microhole 313 with plasticmaterial. The plastic material is illustrated as it is advancing, andhas reached the point at the reference numeral 336. As time proceeds,the plastic material will reach and fill the second microhole 317, whichhas a conical inner wall at 316 and 318, and a corresponding micropillar324.

At the first microhole 313, the plastic material has filled the shapearound a micropillar 322 and within the conical walls of this microhole313, to form a hollow cone having an outer wall at 332 and 334. Theplastic material will be forced upward until it reaches a top point asseen at the reference numerals 370 and 372. The outer conical shape at332 and 334 will converge with the interior shape of the micropillar 322at an angle designated by the angles “A31” and “A32.” Microhole 317 alsoexhibits a converging angular shape at “A33” and “A34,” which is theconvergence angle between the conical walls 316 and 318 and the outercylindrical shape of the micropillar 324.

The separation between the surfaces 328 and 342 is given by the lengthdimension “L35,” which will become the thickness of the planar facematerial that will remain once the mold is opened. The verticaldimension (in FIG. 16) of the microholes is given by the dimension “L31”which preferably will create microneedles long enough to penetratethrough the stratum corneum and into the epidermis, but not so long asto penetrate all the way to the dermis.

FIG. 17 illustrates the microneedle array, generally designated by thereference numeral 380. On FIG. 17, two microneedles are illustrated at382 and 384. These microneedles have a length “L32,” which in theoryshould be exactly the same as the dimension L31 on FIG. 16, assuming themold was properly filled with material. A preferred distance for L32 isin the range of 50-200 microns.

The plastic material 330 has a planar base structure, as illustrated at344, 346, and 348. The thickness of this base structure is the dimensionL35. The microneedles themselves exhibit a conical outer wall at 350 and352 for the left-hand microneedle 382, and at 354 and 356 for theright-hand microneedle at 384. Each microneedle has a hollow interior,as illustrated by the cylindrical surface 360 and 362 for microneedle382, and 364 and 366 for microneedle 384. These surfaces converge toform points (as illustrated on FIG. 17) at 370 and 372 for microneedle382, and at 374 and 376 for microneedle 384. The convergence angle ofthese walls is designated by the angles A31-A34, and preferably will bein the range of zero (0) to forty-five (45) degrees.

The inner diameter of microneedle 382 is given by the dimension D31, andfor microneedle 384 is given by dimension D32. These dimensionspreferably are in the range 1-49, more preferably about 10 microns. Theseparation distance between the center lines of the microneedles isgiven at D33, which preferably is in the range 50-1000 microns, morepreferably about 200 microns. The height L32 is preferably in the rangeof 50-200 microns and, depending upon the convergence angle A31-A34, thebottom width of the conical microneedles will vary depending upon theexact application for usage. In one preferred embodiment, this bottomdimension, designated by “D34” and “D35,” will be approximately twenty(20) microns. The vertical thickness at L35 will likely be made as thinas possible, however, the important criterion is that it is sufficientlythick to be mechanically sound to hold the microneedle array 380together as a single structure during actual usage. It is likely that,for most plastic materials that might be used in this molding procedure,the dimension L35 will be in the range of ten (10) microns through two(2) mm, or greater.

The angular relationship between the microneedles and the correspondingplanar base surface is preferably perpendicular, although an exact rightangle of 90 degrees is not required. This applies to all microneedleembodiments herein described, including microneedles 62, 64 and planarsurfaces 30, 32, 34 of FIG. 6, microneedles 182, 184 and planar surfaces140, 142, 144 of FIG. 11, microneedles 282, 284 and planar surfaces 244,246, 248 of FIG. 15, microneedles 292, 294 and planar surfaces 244, 246,248 of FIG. 15A, microneedles 382, 384 and planar surfaces 344, 346, 348of FIG. 17, and microneedle 470 and planar surfaces 440, 446 of FIG. 21.

It will be understood that other methods of forming plastic microneedlescould be utilized to create hollow microneedles in an array, withoutdeparting from the principles of the present invention. It will also beunderstood that various types of materials could be used for suchmolding procedures, including metallic materials that might be castusing higher temperature dies of a similar shape and size, withoutdeparting from the principles of the present invention.

It will be further understood that variations in dimensions and angularrelationships could be utilized to construct an array of hollowmicroneedles, without departing from the principles of the presentinvention. It will be still further understood that the angularrelationship between the microneedles and their planar base surface neednot be precisely perpendicular (although that configuration ispreferred), but could have some variation without departing from theprinciples of the present invention; the microneedles also need not beexactly parallel with one another, even though that configuration ispreferred.

It will be yet further understood that other microneedle shapes could beused than a cylindrical shape, if desired, without departing from theprinciples of the present invention. Moreover, it will be understoodthat, with only simple modifications to the molds, an array of solidmicroneedles could be fabricated using the molding techniques describedherein, without departing from the principles of the present invention.

While there are conventional hollow needles that can be arranged in anarray, such conventional needles are all much larger in both length anddiameter than those disclosed hereinabove, and therefore, will penetrateall the way into the dermal layer, thereby inflicting a certain amountof pain to the user. Moreover, these larger needles can be made usingmore conventional manufacturing techniques, since their dimensions willallow for a relaxed standard of manufacture.

Referring now to FIG. 18, a procedure for forming dry etchedmicroneedles will be described using an example of microfabrication(e.g., semiconductor fabrication) techniques. Starting with a singlecrystal silicon wafer at reference numeral 400, it is preferred to use adouble side polish wafer and to grow an oxide layer on the entire outersurface. In FIG. 18, a cross-section of this wafer appears as asubstrate 410, a top oxide layer 412, and a bottom oxide layer 414. Anysingle crystal silicon wafer will suffice, although it is preferred touse a crystal structure 100-type wafer, for reasons that will beexplained below. A 110-type wafer could be used, however, it wouldcreate different angles at certain etching steps.

To create the structure depicted in FIG. 19, certain process steps mustfirst be performed, as described below. The first step is a patternoxide step which is performed on the top side only to remove much of thetop oxide layer 412. The pattern used will create multiple annularregions comprising two concentric circles each, of which thecross-section will appear as the rectangles 416 and 418 on FIG. 19. Inperspective, these annular-shaped features will have the appearance asillustrated on the perspective view of FIG. 22 at the reference numerals416 and 418. These annular oxide patterns are the initial stages of thearray locations of the multiple microneedles that will be formed on thissubstrate 410.

The next step is to deposit a layer of silicon nitride using a lowpressure vapor deposition step, which will form a silicon nitride layeron both the top and bottom surfaces of the substrate 410. This appearsas the uppermost layer 420 and the bottommost layer 422 and 424. It willbe understood that the bottommost layer 422 and 424 is one continuouslayer at this step, although it is not illustrated as such on FIG. 19,since a later step etches out a portion of the bottom side of thesubstrate between the layers 422 and 424.

Next in the process is a pattern bottom procedure in which a square holeis patterned beneath the annulus 416, 418, which is not directly visibleon FIG. 19. The square holes placed by the pattern bottom procedure arenow used in a KOH etching step that is applied to the bottom side onlyof the substrate 410. This KOH etching step creates a window along thebottom of the substrate as viewed along the surfaces 432, 430, and 434on FIG. 19. This window interrupts the oxide layer 414 along the bottomof substrate 410, and divides it (on FIG. 19) into two segments 413 and415. This window (or hole) also interrupts the silicon nitride layerinto two segments (on FIG. 19) 422 and 424.

The slope angle of the etched window along surfaces 432 and 434 is 54.7degrees, due to the preferred 100-type silicon material. If type-110silicon material was used, then this slope would be 90 degrees. Thatwould be fine, however, crystalline silicon 100-type material is lessexpensive than silicon 110-type material. After the KOH time etchingstep has been completed, the silicon wafer will have the appearance asdepicted in FIG. 19.

The next fabrication operation is to perform a pattern top nitrideprocedure using a photoresist mask. This removes the entire uppersilicon nitride layer 420 except where the photoresist mask was located,which happens to be aligned with the upper oxide annulus at 416 and 418.The remaining upper silicon nitride is indicated at the referencenumeral 426 on FIG. 20, although at this stage in the fabricationprocedure, the upper surface will still be a planar surface at the levelof the oxide layer 416 and 418, across the entire horizontal dimensionof FIG. 20.

The next fabrication step is to perform a deep reactive ion etch (DRIE)operation on the top surface of the substrate 410, which will etch awaya relatively deep portion of the upper substrate except at locationswhere the silicon nitride layer still remains, i.e., at 426. In thisDRIE procedure, it is preferred to remove approximately 50-70 microns ofmaterial. After that has occurred, the remaining photoresist maskmaterial is removed. This now exposes the top silicon nitride layer 426.

The next fabrication step is to oxidize all of the bare silicon that isnow exposed along the outer surfaces. This will form a layer of silicondioxide at locations on FIG. 20, such as at 440, 442, 444, 446, 452,450, and 454. The outer silicon nitride layers at 426, 423, and 425 arenot oxidized. The outer silicon nitride layers 423 and 425 areessentially the same structures as layers 422 and 424 on FIG. 19,although the silicon dioxide layers 452 and 454 are now formed abovethese “pads” 423 and 425. It is preferred that this oxidation be aminimal amount, just enough for a future DRIE masking procedure, andthat the oxidized thickness be approximately 5,000 Angstroms. At thispoint in the fabrication procedure, the silicon wafer has the appearanceof that depicted in FIG. 20.

The next step in the fabrication procedure is to remove the siliconnitride layer on the top, which will remove the layer at 426 as seen onFIG. 20. This will expose a circular region in the very center of theannulus such that pure silicon is now the outermost material on the topside of the wafer. After that has occurred, a deep reactive ion etchoperation is performed to create a through-hole at the reference numeral460 on FIG. 21. After this step has been performed, there will be puresilicon exposed as the inner wall of the through-hole 460. Therefore,the next step is to oxidize the entire wafer, which will place a thincylindrical shell of silicon dioxide around the inner diameter ofthrough-hole 460, and this oxidized layer is viewed on FIG. 21 at 462and 464.

After these steps have been performed, a microneedle 465 is the result,having an outer diameter at “D41,” and an inner diameter through-hole at“D42.” It is preferred that the inner diameter D42 have a distance inthe range of 5-10 microns. The height of the microneedle is given at thedimension “L41,” which has a preferred dimension in the range of 50-200microns. On FIG. 21, the substrate 410 has been divided into halves at410A and 410B. In addition, the bottom oxide layer 450 has been dividedin halves at 450A and 450B.

The bottom chamber formed by the sloped surfaces 452 and 454, incombination with the horizontal surfaces 450A and 450B, act as a small,recessed storage tank or chamber generally indicated by the referencenumeral 470. This chamber 470 can be used to store a fluid, such asinsulin, that is to be dispensed through the cylindrical opening 460 inthe hollow microneedle 465. At the scale of FIG. 21, this chamber is notvery large in overall physical volume, and it normally would bepreferred to interconnect all of such chambers for each of themicroneedles in the overall array so that a common fluid source could beused to dispense fluid to each of these chambers 470. Furthermore, theremay be a need to dispense a physically much larger volume of fluid, andit also may be desirable to provide a pressure source, such as a pump.In such situations, it may be preferable to have an external storagetank that is in communication with each of the fluid chambers 470 on thewafer that is used to make up the array of microneedles, such asmicroneedle 465.

FIG. 22 depicts an array of microneedles on substrate 410, and alsoillustrates a magnified view of some of these microneedles 465. Eachmicroneedle 465 exhibits a cylindrical shape in the vertical direction,and has an outer diameter D41, an annular shaped upper surface at 416and 418, and a through-hole at 460. Each of the microneedles 465 extendsout from the planar surface 440 of the substrate 410.

As can be seen in FIG. 22, substrate 410 can either be made much largerin height so as to have a very large internal volume for holding a fluidsubstance, or the substrate itself could be mounted onto a differentmaterial that has some type of fluidic opening that is in communicationwith the chambers 470 of the individual microneedles 465.

It will be understood that other semiconductor substances besidessilicon could be used for the fabrication of the array of microneedlesdepicted on FIG. 22, without departing from the principles of thepresent invention. Moreover, other microneedle shapes could be used thana cylindrical shape with an annular top surface, and in fact, the topsurface of such microneedles could be sloped to create a sharper edge,if desired, without departing from the principles of the presentinvention.

It will also be understood that the preferred dimensions discussedhereinabove are only preferred, and any microneedle length or diameterthat is appropriate for a particular chemical fluidic compound and for aparticular skin structure could be used without departing from theprinciples of the present invention. As discussed above, it is preferredthat the microneedle penetrate through the stratum corneum into theepidermis, but not penetrate into the dermis itself. This means thatsuch microneedles would typically be no longer than two hundred (200)microns, though they must typically be at least fifty (50) microns inlength. Of course, if cosmetic applications were desired, then themicroneedle could be much shorter in length, even as short as one (1)micron. Finally, it will be understood that any size or shape offluid-holding chamber could be used in a drug-delivery system, whichwill be further discussed hereinbelow. In addition, for a body-fluidsampling system, a fluid-holding chamber would also preferably be incommunication with the through-holes 460 of each of the microneedles465.

FIG. 23 depicts an iontophoretically enhanced body-fluid sensor that isbased upon a hollow microneedle array, generally designated by thereference numeral 500. Sensor 500 includes a plurality of microneedles530, which are each hollow, having a vertical opening throughout, asindicated at 532. A fluid chamber 510 is in communication with thehollow portions 532 of the array of microneedles 530.

Fluid chamber 510 is constructed of a bottom (in FIG. 23) planar surface512—which has openings that are aligned with the microneedles 530—a leftvertical wall 514, and a right vertical wall 516. The top (or ceiling)of the fluid chamber 510 is made up of a planar material which isdivided into individual electrodes. The middle electrode 525 is part ofthe fluid sensor, and makes it possible to measure a current or voltagewithin the fluid chamber 510. Electrodes 520 and 522 are electricallyconnected to one another (and can be of a single structure, such as anannular ring) so as to act as the iontophoretic electrodes (i.e., aseither an anode or a cathode) that facilitate the transport of fluidthrough the hollow microneedles 530 from the skin into the fluid chamber510.

The height of the fluid chamber structure is designated as “L50,” whichcould be any reasonable dimension that is large enough to hold asufficient volume of fluid for a particular application. Of course, ifdesired, the fluid chamber 510 could be connected to a much largerexternal reservoir (not shown), and a pump could even be used ifpressure or vacuum is desired for a particular application.

The layer 540 represents the stratum corneum, the layer 542 representsthe viable epidermis, and the largest layer 544 represents the dermis,which contains nerves and capillaries.

The application of microneedles 530 into the stratum corneum 540 andepidermis 542 decreases the electrical resistance of the stratum corneumby a factor of approximately fifty (50). The applied voltage, therefore,during iontophoresis can be greatly reduced, thereby resulting in lowpower consumption and improved safety. Iontophoresis provides thenecessary means for molecules to travel through the thicker dermis intoor from the body. The combination of the microneedles and the electricfield that is applied between the electrodes 520 and 522 (acting as ananode, for example) and a remotely placed electrode (e.g., electrodeassembly 505, viewed on FIG. 25, and acting as a cathode, for example)provides for an increase in permeability for both the stratum corneumand the deeper layers of skin.

While the transport improvement in stratum corneum is mostly due tomicroneedle piercing, the iontophoresis provides higher transport ratesin the epidermis and dermis. This is not only true for small sizedmolecules, but also for the larger and more complex useful molecules.

The body-fluid sampling sensor 500 can be used for a continuousnon-invasive measurement of blood glucose level, for example. Glucose isextracted through the skin by reverse iontophoresis, and itsconcentration is then characterized by a bioelectrochemical sensor. Thesensor comprises the chamber 510 that is filled with hydrogel andglucose oxidase, and the electrode 525. The glucose molecules are movedfrom the body by the flow of sodium and chloride ions caused by theapplied electric potential. The detection of the glucose concentrationin the hydrogel pad is performed by the bioelectrochemical sensor.

An alternative embodiment 550 is depicted in FIG. 24, in which themicroneedles 580 are solid, rather than hollow. A fluid-filled chamber560 is provided and also comprises hydrogel filled with glucose oxidase.The chamber 560 is made of a bottom wall 562 that has openings proximalto the individual microneedles 580, in which these openings aredesignated by the reference numeral 585. Chamber 560 also includes sidewalls 564 and 566, as well as electrodes 570, 572, and 575.

The electrode 575 is constructed as part of the bioelectrochemicalsensor. The electrodes 570 and 572 act as the iontophoretic electrodes,acting either as an anode or cathode to set up an electric currentthrough the skin which flows to a remotely-attached (to the skin)electrode (e.g., electrode assembly 555, viewed on FIG. 26).

As in the sensor 500 of FIG. 23, the transport rate of fluids isenhanced by not only the piercing effect of the microneedles 580, butalso the electric field inducing a current through the skin. In theglucose sampling example, glucose is attracted into the chamber 560, andits concentration is measured by the bioelectrochemical sensor.

The height of the fluid chamber structure is designated as “L55,” whichcould be any reasonable dimension that is large enough to hold asufficient volume of fluid for a particular application. Of course, ifdesired, the fluid chamber 560 could be connected to a much largerexternal reservoir (not shown), and a pump could even be used ifpressure or vacuum is desired for a particular application.

FIG. 25 depicts an iontophoretic electrode assembly that is based upon ahollow microneedle array, generally designated by the reference numeral505. Electrode assembly 505 includes a plurality of microneedles 531,each being hollow and having a vertical opening throughout, as indicatedat 533. A fluid chamber 511 is in communication with the hollow portions533 of the array of microneedles 531.

Fluid chamber 511 is constructed of a bottom planar surface 513—whichhas openings that are aligned with the microneedles 531—a left verticalwall 515, and a right vertical wall 517. The top (or ceiling) of fluidchamber 511 is made of a planar electrode material 526. The electrode526 is to be electrically connected to a low-current voltage source (notshown on FIG. 25), either through a substrate pathway (such as aintegrated circuit trace or a printed circuit foil path) or a wire (alsonot shown on FIG. 25).

The height of the fluid chamber 511 is given by the dimension “L52,”which can be of any practical size to hold a sufficient amount ofhydrogel, for example, to aid in the conduction of current while actingas the electrode. In electrode assembly 505, the fluid within chamber511 preferably would not be electrically charged.

As can be seen in FIG. 25, the hollow microneedles 531 penetrate thestratum corneum 540 and into the viable epidermis 542. The microneedles531 preferably will not be sufficiently long to penetrate all the way tothe dermis 544.

An alternative embodiment 555 is depicted in FIG. 26, in which themicroneedles 581 are solid, rather than hollow. A fluid chamber 561 isprovided and preferably is filled with hydrogel (which is notelectrically charged). Chamber 561 is made of a bottom wall 563 that hasopenings proximal to the individual microneedles 581, in which theseopenings are designated by the reference numeral 586. Chamber 561 alsoincludes side walls 565 and 567, as well as a top (or ceiling) electrode576. The electrode 576 may act as a cathode, for example, in a situationwhere electrode assembly 555 is being used in conjunction with abody-fluid sensor, such as sensor assembly 550 viewed on FIG. 24, inwhich its electrodes 570 and 572 may act, for example, as an anode. Theheight “L57” of fluid chamber 561 could be any reasonable dimension thatis large enough to hold a sufficient volume of the hydrogel to enhancethe fluid flow via the electric field between the respective anode andcathode of the system.

FIG. 27 illustrates a portion of a human arm and hand 590, along with adrug delivery electrode assembly 500 and a second electrode assembly505. Both electrodes are attached to the skin of the human user, viatheir microneedles, such as the hollow microneedles 530 (viewed on FIG.23) and the hollow microneedles 531 (viewed on FIG. 25).

Since an electrical voltage is applied between the two electrodeassemblies 500 and 505, it is preferred to use a low current powersupply, generally designated by the reference numeral 596, that isconnected to each of the electrodes via a wire 592 or a wire 594,respectively. It will be understood that any type of physical electricalcircuit could be used to provide the electrical conductors and powersupply necessary to set up an appropriate electrical potential, withoutdeparting from the principles of the present invention. In fact, theelectrode assemblies and wiring, along with an associated power supply,could all be contained on a single apparatus within a substrate, such asthat viewed on FIGS. 30 and 31 herein, or by use of printed circuitboards.

FIG. 28 depicts an iontophoretically enhanced fluidic drug deliveryapparatus that is based upon a hollow microneedle array, generallydesignated by the reference numeral 600. Drug-delivery apparatus 600includes a plurality of microneedles 630, which are each hollow, havinga vertical opening throughout, as indicated at 632. A fluid chamber 610is in communication with the hollow portions 632 of the array ofmicroneedles 630.

Fluid chamber 610 is constructed of a bottom (in FIG. 28) planar surface612—which has openings that are aligned with the microneedles 630—a leftvertical wall 614, and a right vertical wall 616. The top (or ceiling)of the fluid chamber 610 is made up of a planar material 620 that actsas an electrode. Electrode 620 is part of the drug delivery apparatus,and makes it possible to induce a current flow through fluid chamber610. Electrodes 620 and 622 are connected so as to act as theiontophoretic electrodes (i.e., as either an anode or a cathode) thatfacilitate the transport of fluid through the hollow microneedles 630from the fluid chamber 610 into the skin.

The height of the fluid chamber structure is designated as “L60,” whichcould be any reasonable dimension that is large enough to hold asufficient volume of fluid for a particular drug delivery application.Of course, if desired, the fluid chamber 510 could be connected to amuch larger external reservoir (not shown), and a pump could even beused if pressure or vacuum is desired for a particular application.

The layer 540 represents the stratum corneum, the layer 542 representsthe viable epidermis, and the largest layer 544 represents the dermis,which contains nerves and capillaries.

The application of microneedles 630 into the stratum corneum 540 andepidermis 542 decreases the electrical resistance of the stratum corneumby a factor of approximately fifty (50). The applied voltage, therefore,during iontophoresis can be greatly reduced, thereby resulting in lowpower consumption and improved safety. Iontophoresis provides thenecessary means for molecules to travel through the thicker dermis intoor from the body. The combination of the microneedles and the electricfield that is applied between the electrodes 620 and 622 (acting asanodes, for example), and another electrode (e.g., electrode assembly505, acting as a cathode) that is attached elsewhere on the skin of theuser, provides for an increase in permeability for both the stratumcorneum and the deeper layers of skin. While the transport improvementin stratum corneum is mostly due to microneedle piercing, theiontophoresis provides higher transport rates in the epidermis anddermis. This is not only true for small sized molecules, but also forthe larger and more complex useful molecules.

The drug delivery apparatus 600 can be used for a continuousnon-invasive medical device that can continuously deliver a fluidic drugthrough the skin and into the body. For example, insulin could bedelivered to the blood stream via the microneedles 531, through thestratum corneum 540 and epidermis 542, and also into the dermis 544where the insulin would be absorbed into the capillaries (not shown).

An alternative embodiment 650 is depicted in FIG. 29, in which themicroneedles 680 are solid, rather than hollow. A fluid-filled chamber660 is provided and also contains hydrogel. Chamber 660 is made of abottom wall 662 that has openings proximal to the individualmicroneedles 680, in which these openings are designated by thereference numeral 685. Chamber 660 also includes side walls 664 and 666,as well as electrodes 670, 672, and 675.

The electrode 675 is constructed as part of the bioelectrochemicalsensor. The electrodes 670 and 672 act as the iontophoretic electrodes,acting either as the anode or cathode to set up an electric currentthrough the skin, in conjunction with another electrode assembly (suchas electrode assembly 655, viewed on FIG. 26) placed elsewhere on theuser's skin.

As in the drug delivery apparatus 600 of FIG. 28, the transport rate offluids is enhanced by not only the piercing effect of the microneedles680, but also the electric field inducing a current through the skin. Inthe insulin dispensing example, insulin is repelled from the chamber660, and therefore, flows out through openings 685 proximal tomicroneedles 680, then into the user's skin.

The height of the fluid chamber structure is designated as “L65,” whichcould be any reasonable dimension that is large enough to hold asufficient volume of fluid for a particular application. Of course, ifdesired, the fluid chamber 660 could be connected to a much largerexternal reservoir (not shown), and a pump could even be used ifpressure or vacuum is desired for a particular application.

FIG. 30 depicts a closed-loop drug-delivery system generally designatedby the reference numeral 700. This closed-loop system 700 includes apair of iontophoretic pads, generally designated by the referencenumerals 500 and 505, which each include an array of microneedles forfluid sampling. Pad 500 comprises a sensor assembly (as describedhereinabove with respect to FIG. 23), and pad 505 comprises an electrodeassembly (as described hereinabove with respect to FIG. 25).

Closed-loop system 700 also includes a pair of iontophoretic pads,generally designated by the reference numerals 600 and 605, that eachinclude an array of microneedles for drug delivery. Pad 600 comprises adrug delivery apparatus (as described hereinabove with respect to FIG.28), and pad 505 comprises an electrode assembly (as describedhereinabove with respect to FIG. 25). Of course, iontophoretic padshaving solid microneedles could instead be used, such that pads 500 and600 (with hollow microneedles) could be replaced by pads 550 and 650(with solid microneedles), and pad 505 (with hollow microneedles) couldbe replaced by a pad 555 (with solid microneedles).

Pads 500 and 600 are mounted to a substrate 710, which can be made ofeither a solid or a somewhat flexible material. Within substrate 710preferably resides a reservoir 712 (within the substrate 710) that holdsthe fluid which is to be dispensed through the microneedles of pads 600.Reservoir 712 could be made up of individual “small” chambers, such as alarge number of chambers 610 that are connected to a source of fluidicdrug.

It will be understood that the reservoir 712 preferably is completelycontained within substrate 710, and cannot be seen from this view ofFIG. 31. As an alternative, however, a fluid channel (such as a flexibleat 730) could be connected into substrate 710 and, by use of a pump (notshown), further quantities of the fluid could be provided and dispensedthrough the microneedles of pads 600, using fluidic pressure.

FIG. 31 illustrates the opposite side of the closed-loop system 700. Acontroller 720 is mounted to the upper surface (in this view) ofsubstrate 710. Controller 720 preferably comprises a type of microchipthat contains a central processing unit that can perform numericcalculations and logical operations. A microprocessor that executessoftware instructions in a sequential (or in a parallel) manner would besufficient. A microcontroller integrated circuit would also suffice, oran ASIC that contains a microprocessor circuit.

Adjacent to controller 720 is an iontophoretic power supply with abattery, the combination being generally designated by the referencenumeral 722. In addition, a visual indicator can be placed on thesurface of the substrate, as at 730. This visual indicator could give adirect reading of the quantity of interest, such as glucoseconcentration, or some other body-fluid parameter. The visual indicatorpreferably comprises a liquid crystal display that is capable ofdisplaying alphanumeric characters, including numbers.

While a pumping system that creates fluid pressure could be used fordispensing a fluidic drug into a body through hollow microneedles, suchas emplaced on pads 600, it is preferred to use an iontophoresis methodto enhance the delivery of the drugs through the microneedles. Asdiscussed hereinabove, application of microneedles can decrease theelectrical resistance of the stratum corneum by a factor of fifty (50),and so the voltage necessary to facilitate iontophoresis can be greatlyreduced, improving safety and requiring much less power consumption. Byuse of the iontophoresis, the molecules making up the fluid drug willtravel through the thicker dermis into or from the body, and thecombination of both transport-enhancing methods provides an increase inpermeability for both the stratum corneum and the deeper layers of theskin. The transport improvement in the stratum corneum is mostly due tomicroneedle piercing, although the iontophoresis provides highertransport rates in the epidermis and dermis.

The closed-loop drug-delivery system and fluid-sampling system 700 canbe used for continuous noninvasive measurement of blood glucose level byextracting, via reverse iontophoresis, glucose through the skin andmeasuring its concentration by the bioelectrochemical sensor (such asthe sensor constructed of the hydrogel chamber 510 and sensor electrode525, along with the controller 720). The hydrogel pads containingmicroneedles (i.e., pads 500) enhance the reverse iontophoresis to moveglucose molecules from the body by the flow of sodium and chloride ions,which are caused by the applied electric potential via electrodes 520and 522. Once the glucose concentration is measured within the hydrogelpads 500, the proper amount of insulin, for example, can be dispensedthrough the other pair of pads 600 that make up part of the closed-loopsystem 700.

As discussed hereinabove, drug delivery is performed by applying anelectric potential between two microneedle array electrodes. One of theelectrodes is filled with an ionized drug (such as insulin), and thecharged drug molecules move into the body due to the electric potential.Controller 720 will determine how much of a drug is to be dispensedthrough the microneedle array 600 at any particular time, thereby makingthe closed-loop system 700 a “smart” drug-delivery system.

This smart drug-delivery system can be used as an artificial pancreasfor diabetes patients, as a portable hormone-therapy device, as aportable system for continuous out-patient chemotherapy, as asite-specific analgesic patch, as a temporary and/or rate-controllednicotine patch, or for many other types of drugs. Such systems could bemade as a disposable design, or as a refillable design.

It will be understood that the closed-loop system 700 can be used inmany applications, including as a painless and convenient transdermaldrug-delivery system for continuous and controlled outpatient therapies,a painless and convenient body-fluid sampling system for continuous andprogrammed outpatient body-fluid monitoring, as a high-rate transdermaldrug delivery system, or as a high-accuracy transdermal body-fluidsampling system. More specifically, the closed-loop system 700 of thepresent invention can be used as a portable high-accuracy painlesssensor for outpatient blood glucose-level monitoring, as a portablesystem for continuous or rate controlled outpatient chemotherapy, as atemporary and rate controlled nicotine patch, as a site-specificcontrolled analgesic patch, as an externally attached artificialpancreas, as externally attached artificial endocrine glands, astemperature-controlled fever-reducing patches, as heart rate-controllednitroglycerin high-rate transdermal patches, as temporarily controlledhormonal high-rate transdermal patches, as erectile dysfunctiontreatment high-rate transdermal patches, and as a continuous accurateblood-analysis system. Another use of the closed-loop system 700 of thepresent invention is to form a portable drug delivery system foroutpatient delivery of the following drugs and therapeutic agents, forexample: central nervous system therapy agents, psychic energizingdrugs, tranquilizers, anticonvulsants, muscle relaxants andanti-parkinson agents, smoking cessation agents, analgetics,antipyretics and anti-inflammatory agents, antispasmodics and antiulceragents, antimicrobials, antimalarias, sympathomimetric patches,antiparasitic agents, neoplastic agents, nutritional agents, andvitamins.

It will be understood that various materials other than those disclosedhereinabove can be used for constructing the closed-loop system 700, andfor constructing individual body-fluid sampling sensors and individualdrug-delivery systems. Such other materials could include diamond,bio-compatible metals, ceramics, polymers, and polymer composites,including PYREX®. It will yet be further understood that theiontophoretically/microneedle-enhanced transdermal method of transportof the present invention can also be combined with ultrasound andelectroporation, in order to achieve high-rate drug delivery intoindividual cells.

It will also be understood that the length of the individualmicroneedles is by far the most important dimension with regard toproviding a painless and bloodless drug-dispensing system, or a painlessand bloodless body-fluids sampling system using the opposite directionof fluid flow. While the dimensions discussed hereinabove are preferred,and the ranges discussed are normal for human skin, it will further beunderstood that the microneedle arrays of the present invention can beused on skin of any other form of living (or even dead) creatures ororganisms, and the preferred dimensions may be quite different ascompared to those same dimensions for use with human skin, all withoutdeparting from the principles of the present invention.

It yet will be understood that the chemicals and materials used in themolds and dies can be quite different than those discussed hereinabove,without departing from the principles of the present invention. Further,it will be understood that the chemicals used in etching and layeringoperations of microfabrication discussed above could be quite differentthan those discussed hereinabove, without departing from the principlesof the present invention.

The foregoing description of a preferred embodiment of the invention hasbeen presented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed. Obvious modifications or variations are possible in light ofthe above teachings. The embodiment was chosen and described in order tobest illustrate the principles of the invention and its practicalapplication to thereby enable one of ordinary skill in the art to bestutilize the invention in various embodiments and with variousmodifications as are suited to the particular use contemplated. It isintended that the scope of the invention be defined by the claimsappended hereto.

What is claimed is:
 1. A structure comprising a base element andplurality of microneedles formed thereon, wherein said base element hasa first side and a second side; wherein said plurality of microneedlescomprises a plurality of hollow elements which project from the secondside of said base element along a longitudinal axis that is at an anglewith respect to said base element; wherein at least one of saidlongitudinal axes of said microneedles is in alignment with one of aplurality of first openings in the second side of said base element;wherein said hollow elements of said plurality of microneedles allowliquid to flow therethrough between a plurality of second openings at adistal end of said hollow elements and said first openings at the secondside of said base element; and a container structure comprising: (a) areservoir capable of holding a liquid, (b) a first electrode proximal tosaid reservoir, (c) an electrical power source that is in communicationwith said electrode, and (d) a second electrode proximal to saidreservoir at a location different than said first electrode, said secondelectrode detecting an electrical signal in the manner of abioelectrochemical sensor.
 2. The structure as recited in claim 1,wherein said hollow elements are tubular in shape.
 3. The structure asrecited in claim 1, wherein said hollow elements are conical in shape.4. The structure as recited in claim 1, wherein said first or saidsecond electrode of said container structure facilitates dispensing anionized liquid from said reservoir through said plurality ofmicroneedles into skin by iontophoresis.
 5. The structure as recited inclaim 1, further comprising an electronic controller; wherein said firstor said second electrode facilitates body-fluid sampling of a body fluidfrom skin through said plurality of microneedles by reverseiontophoresis.
 6. The structure as recited in claim 1, wherein saidsignal detected by said second electrode provides an indication of aconcentration of a sampled body-fluid.
 7. A structure comprising a baseelement and plurality of microneedles formed thereon, wherein said baseelement has a first side and a second side; wherein said plurality ofmicroneedles comprises a plurality of solid projections which extendfrom the second side of said base element along a longitudinal axis thatis at an angle with respect to said base element; and wherein at leastone of said longitudinal axes of said microneedles is located proximalto a plurality of openings in the second side of said base element, suchthat there are individual of said openings near each one of saidprojections; and wherein said plurality of microneedles allows liquid toflow along their outer surfaces through said openings at the second sideof said base element; and a container structure comprising: (a) areservoir capable of holding a liquid, (b) an electrode proximal to saidreservoir, and (c) an electrical power source that is in communicationwith said electrode.
 8. The structure as recited in claim 7, whereinsaid openings are smaller in cross-section than said solid projections.9. The structure as recited in claim 7, wherein there is at least one ofsaid openings for each of said plurality of projections.
 10. Thestructure as recited in claim 7, wherein the electrode of said containerstructure facilitates dispensing an ionized liquid from said reservoirthrough said plurality of microneedles into skin by iontophoresis. 11.The structure as recited in claim 10, further comprising an externalliquid storage tank that is in fluidic communication with saidreservoir, and a fluid channel structure that transports liquid fromsaid external liquid storage tank to said reservoir.
 12. The structureas recited in claim 7, further comprising an electronic controller;wherein said electrode facilitates body-fluid sampling of a body fluidfrom skin through said plurality of microneedles by reverseiontophoresis.
 13. The structure as recited in claim 12, furthercomprising a second electrode proximal to said reservoir at a locationdifferent than said first electrode, said second electrode detecting anelectrical signal in the manner of a bioelectrochemical sensor.
 14. Thestructure as recited in claim 13, wherein said the signal detected bysaid second electrode provides an indication of a percentageconcentration of a sampled body-fluid.
 15. The structure as recited inclaim 12, wherein said electrical power source includes a battery, andsaid electronic controller includes a central processing circuit; andfurther comprising a visual indicator.
 16. An integral structurecomprising a base element and plurality of microneedles formed thereon,wherein said base element has a first side and a second side; saidplurality of microneedles comprising a plurality of solid projectionswhich extend from the second side of said base element alonglongitudinal axes that are at an angle with respect to said baseelement; and a first plurality of openings in the second side of saidbase element, such that there are individual of said openings near eachone of said projections, said openings being of a sufficient size so asto allow liquid to flow therethrough.
 17. The structure as recited inclaim 16, wherein said liquid passes from said first plurality ofopenings at the second side of said base element and into skin, by wayof diffusion.
 18. The structure as recited in claim 16, furthercomprising: (a) a reservoir for holding a liquid that is to bedispensed, (b) an electrode proximal to said reservoir at a firstlocation, and (c) an electrical power source that is in communicationwith said electrode; wherein said electrode facilitates dispensing saidliquid into skin by iontophoresis.
 19. The structure as recited in claim16, further comprising: (a) a reservoir for holding a liquid that is tobe sampled, (b) a first electrode proximal to said reservoir at a firstlocation, (c) a second electrode proximal to said reservoir at a secondlocation which detects an electrical signal in the manner of abioelectrochemical sensor, (d) an electrical power source that is incommunication with said first electrode, and (e) an electroniccontroller; wherein said first electrode facilitates body-fluid samplingof a body fluid from skin by reverse iontophoresis.
 20. The structure asrecited in claim 16, wherein said microneedles exhibit a length alongsaid longitudinal axis in the range of 100 microns through 200 microns.21. The structure as recited in claim 16, wherein said microneedlesexhibit a length along said longitudinal axis in the range of 1 micronsthrough 5 microns.
 22. The structure as recited in claim 16, whereinsaid microneedles exhibit an inner diameter in the range of 1-49microns.
 23. The structure as recited in claim 16, wherein saidmicroneedles exhibit an outer diameter in the range of 1-50 microns. 24.The structure as recited in claim 16, further comprising: (a) areservoir for holding a liquid that is to be dispensed, (b) a pressuresource that is in communication with said reservoir; wherein saidpressure source facilitates dispensing said liquid along the surface ofsaid plurality of microneedles into skin by applying a fluidic pressurethereto.
 25. The structure as recited in claim 16, wherein saidplurality of microneedles allows liquid to flow along their outersurfaces through said first plurality of openings at the second side ofsaid base element.